In both nondiabetic and diabetic patients, hyperglycemia and insulin resistance commonly complicate critical illness. Even moderate hyperglycemia, at levels that conventionally have not been treated acutely with insulin because of the risk of inducing hypoglycemia, contributes to morbidity and mortality. A recent randomized clinical trial in critically ill patients demonstrated that intensive insulin therapy to tightly control blood glucose concentration (80 - 110 mg/dL) substantially reduced morbidity and mortality by more than 40% (from 8.0% to 4.6%) but was associated with a 5.0% incidence of severe hypoglycemia (glucose concentration < 40 mg/dL). Therefore, in critically ill patients, continuous glucose monitoring, ideally noninvasive, would be invaluable to guide insulin infusion to both control hyperglycemia and avoid hypoglycemia. For this purpose, optical coherence tomography (OCT) based on low-coherence interferometry, a high-resolution optical technique that sensitively detects photons coherently scattered from tissue, is highly promising. We have developed a novel, OCT-based glucose sensor that precisely, continuously and noninvasively measures the decrease of tissue light scattering that linearly accompanies increases of blood glucose concentration. During the past two years, supported by an NIDDK R-21 grant under the PA-99-036 ("Pilot and Feasibility Program in Diabetes Endocrinology and Metabolism"), we performed preliminary animal and clinical studies of the novel glucose sensor. Our studies demonstrated: 1) a sharp and linear decrease of the OCT signal slope in skin and oral mucosa as blood glucose concentration increased; and 2) substantial improvement of accuracy of the OCT signal slope measurement by optimizing the dimensions of the probed tissue area. The goals of the proposed project are: (1) to further refine the glucose sensor in animal studies; and (2) to validate the resulting sensor in clinical studies in normal subjects and critically ill patients. Successful implementation of the project will produce a continuous, noninvasive, and accurate glucose sensor that will substantively contribute to reduced mortality and morbidity in critically ill patients.